Cytokines are biologically active, soluble polypeptide mediators which control the differentiation, activation and proliferation of various cell types of the immune system, for example the induction or modulation of macrophage functions. Examples of cytokines are the well characterized interferons, interleukins and colony stimulating factor, as well as macrophage migration inhibition factor (MIF) and macrophage activation factor (MAF) that display macrophage inhibition or activation properties, respectively.
Numerous activities have been attributed to cytokines although few of these can be ascribed to single molecules. For example, human MIF, which is thought to consist of a group of polypeptides, is defined in vitro in an assay which measures the inhibition of random migration of macrophages. In vivo, human MIF plays an important role in the early events of cellular immune reactions ("delayed type hypersensitivity") by its mediation of macrophage functions. Generally, the first exposure of a patient to an antigen produces no noticeable change, but the immune status of the recipient is clearly altered. Upon second contact with the antigen, the delayed hypersensitivity reaction is manifested by the infiltration of cells, beginning with a perivascular accumulation of lymphocytes and monocytes at the site where the antigen is located. Some of these cells are specifically sensitized as a result of the first contact with the antigen. These cells react with the antigen, which causes release of lymphokines and the attraction and retention of large numbers of unsensitized cells. In particular, it is assumed that the production of MIF results in the attraction of monocytes which pass through the endothelium of the blood vessel wall and enter the surrounding tissue. Concomittantly with this infiltration, the monocytes differentiate into tissue macrophages. The macroscopic phenomena seen in delayed type hypersensitivity are swelling at the site of contact with the antigen caused by cellular infiltration and reddening caused by dilatation of the underlying blood vessels. Under normal conditions, the inflammatory reaction will cease after about two to three days when possible tissue damage has been repaired. However, for unknown reasons, inflammations can become chronic, causing extensive tissue damage, e.g. rheumatoid arthritis. A possible explanation for the generation of chronic inflammation could be that, at the onset, the differentiation of the infiltrate macrophages has been deregulated.